Rett Syndrome (RS) is a severe neurodevelopmental disorder with a characteristic constellation of stereotyped movements, seizures, and cognitive decline that affects girls almost exclusively. Based on the unique clinical sequence in which early postnatal regression is followed by stabilization; pathological changes suggestive of prenatal involvement; and evidence of selective vulnerability of subsets of neurons, particularly in the dopaminergic and cholinergic systems in basal ganglia and basal forebrain region; a hypothesis is formulated that RS is a genetic disorder of prenatal onset followed postnatally by a failure of telencephalic growth. Further, based on our finding of increased NMDA receptor density in selected regions of the brain, the hypothesis will be examined that neuroexcitotoxic injury from glutamatergic neurotransmitters is responsible for the striking early neurodegenerative phase between 1-3 years (RS stage II). This application for continuation of the program project has the following components: Naidu will identify classic cases, document the natural history including utilization of quantitative imaging techniques described in project 4, search for a biochemical or genetic marker, and consider new treatment approaches. Bauman/Kaufmann will utilize gapless serial section and conventional as well as histochemical techniques to assess pathological alterations in all brain regions and identify subsets of neurons that have selective vulnerability. Johnston et al will use neurochemical and neuroanatomic techniques to define in more detail the neurodegenerative phase that occurs in the rapidly progressive stage II of RS; and compare them to those in animal models that replicate alterations in the dopaminergic and cholinergic neuronal systems seen in RS. Potential therapeutic interventions with neurotrophic factors will be tested in this model. Wong will perform serial volumetric and vector MRI analyses in order to quantify the evolution of abnormalities. These will be correlated with clinical progression (Naidu) and neuropathology Bauman/Kaufmann. PET studies will focus on the regions and neurotransmitter pathways that appear to be affected most severely, namely the nigrostriatal dopaminergic pathways, and attempt to identify NMDA-- induced effects on intrasynaptic dopamine. Taken together, these complementary projects should provide greater understanding of the mechanisms underlying RS, and permit development of specific, rational therapy for this disorder, which is the ultimate goal of this program project.